Severe combined immunodeficiency diseases (SCIDs) represent a spectrum of disorders characterized by profound defects of both cellular and humoral immunity (Cooper, M. D. and Butler, J. L. Fundamental Immunology, (Paul, W. E., editor, Raven Press, New York), pp. 1034-1039 (1989); Gelfand, E. W. and Dosch, H. M. Birth Defects: Original Article Series 19(3): 65-72 (1983); Conley, M. E. Annu. Rev. Immunol. 10: 215-238 (1992)). One in every 10.sup.5 to 10.sup.6 live births are affected by these diseases. Infants with SCID usually become ill in the first few months of life. While their growth and development may initially proceed normally, infections leading to cessation of growth soon become evident (Cooper, M. D. and Butler, J. L., supra, at 1034). Individuals with SCID are vulnerable to virtually every type of pathogenic microorganism, even those that rarely cause disease in normal individuals (Cooper, M. D. and Butler, J. L., supra, at 1034). Candida fungal infection of mucocutaneous surfaces is often the first indication of immunodeficiency, followed by intractable diarrhea and pneumonia (Cooper, M. D. and Butler, J. L., supra, at 1034). The majority of infected infants die before their first birthday.
Classical SCID ("Swiss-type agammaglobulinemia") is characterized by the absence of both T and B cells, presumably related to a defect affecting the lymphocytic stem cell. Autosomal recessive forms of SCID result from deficiencies of adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP), the inability to express class II molecules of the major histocompability complex ("Bare Lymphocyte Syndrome"), or defective IL-2 production. Other autosomal recessive forms have no known defect (Cooper, M. D. and Butler, J. L., supra, at 1034-1037; Gelfand, E. W. and Dosch, H. M., supra, at 66-67; Conley, supra, at 215-238).
X-linked severe combined immunodeficiency (XSCID) accounts for approximately half of all cases of SCID. This form of SCID is inherited in an X-linked fashion. XSCID is characterized by an absence of T-cells and histologic evidence of hypoplastic and abnormal differentiation of the thymic epithelium. Levels of B-cells are normal or even elevated, and therefore patients are only mildly lymphopenic (Cooper, M. D. and Butler, J. L., supra, at 1037; Gelfand, E. W. and Dosch, H. M., supra, at 66-70; Conley, M. E., supra, at 226-227). Since the B-cells are not functional, these males are hypo- or agammaglobulinemic.
In U.S. Ser. No. 08/031,143, filed Mar. 12, 1993, U.S Pat. No. 5,518,880 and in Noguchi, M., et al. Cell 73: 147-157 (1993), it was determined that XSCID results from a defective or mutated IL-2R.gamma. gene.
Human IL-2R.alpha. (Leonard, W. J., et al. Nature (London) 311: 625-631 (1984); Nikaido, T., et al. Nature (London) 311: 631-635 (1984)), IL-2R.beta. (Hatakcyama, M., et al. Science 244: 551-556 (1989)), and IL-2R.gamma. (Takeshita, T., et al. Science 257: 379-382 (1992)) cDNAs have been isolated. Murine cDNAs, however, have only been isolated for IL-2R.alpha. (Miller, J., et al. J. Immunol. 134: 4212-4217 (1985); Shimuzu, A., et al. Nucleic Acids Res. 13: 1505-1516 (1985)) and IL-2R.beta. (Kono, T., et al. Proc. Natl. Acad. Sci. USA 87: 1806-1810 (1990)).
The present invention is based upon the isolation of murine IL-2R.gamma. cDNA, and its uses thereof. One important application of the murine IL-2R.gamma. cDNA is the preparation of an IL-2R.gamma. deficient mouse. The IL-2R.gamma. deficient mouse should serve as an excellent animal model for XSCID.